Note Cite This: J. Org. Chem. 2018, 83, 14802−14810
pubs.acs.org/joc
Copper-Catalyzed Multicomponent Domino Reaction of 2‑Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium Azide: Access to 1H‑[1,2,3]Triazolo[4,5‑c]quinoline Derivatives Cheng Xu,† Shi-Fen Jiang,† Yan-Dong Wu,† Feng-Cheng Jia,*,‡ and An-Xin Wu*,† †
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Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ‡ School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, P. R. China S Supporting Information *
ABSTRACT: A practical copper-catalyzed multicomponent reaction has been developed for the synthesis of 1H-[1,2,3]triazolo[4,5c]quinoline derivatives from commercially available 2-bromobenzaldehydes, aryl methyl ketones, and sodium azide. This protocol integrated consecutive base-promoted condensation, [3 + 2] cycloaddition, copper-catalyzed SNAr, and denitrogenation cyclization sequences. Preliminary mechanistic studies revealed that CuBr2 acted as a multifunctional catalyst to streamline this domino process. The mild catalytic system enabled effective construction of one C−C and four C−N bonds in one operation.
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mainly includes the following two types: (i) 1,3-Dipole cycloaddition reactions of NaN3 with electron-deficient olefins11 or alkynes;12 and (ii) copper-catalyzed coupling reactions of NaN3 with aryl halides13 involving concomitant N atom transfer reaction.14 Great achievements have been made in the field of employing NaN3 as a versatile building block based on the two typical reaction patterns.15,16 However, illustrations for the construction of N-containing heterocycles using NaN3 as a dual nitrogen source remain rare. In 2015, we developed an appealing copper-catalyzed domino protocol for the rapid synthesis of 5-phenyl-[1,2,3]triazolo[1,5-c]quinazoline derivatives from readily available (E)-1-bromo-2(2-nitrovinyl)benzenes, aldehydes, and NaN3 (Scheme 1a).17 Moreover, we have also disclosed an efficient Fe/Cu relaycatalyzed domino protocol for the synthesis of 2-phenyl-
he pursuit of concise synthetic methods that enable the rapid, straightforward construction of multifarious heterocyclic frameworks with structural novelty and complexity is the key focus of organic synthesis and drug discovery.1 In this context, catalytic multicomponent reactions2 have proven to be extremely powerful protocols that allow the convergent synthesis of complex molecules from relatively simple substrates through facile formation of multiple covalent bonds in a single operation. A large number of corresponding methodologies have been established for the construction of N-containing heterocycles.3 The 1,2,3-triazole nucleus is a privileged structural motif that has been widely applied in the materials,4 chemical,5 and biological sciences.6 In particular, triazole-fused polycyclic heterocycles7 are extremely attractive owing to their remarkable pharmaceutical and biological functionalities. They have been reported to show good serine protease inhibition activity,8a antimicrobial effects,8b,c and promising anticancer properties.8d 1H-[1,2,3]Triazolo[4,5c]quinolines are a class of structurally novel triazole-fused heterocycles that contain both 1,2,3-triazole and quinoline frameworks. It is assumed that this novel hybrid skeleton may feature promising bioactivity for screening considering analogue fused 1,2,3-triazoles and their component units. However, only a few synthetic approaches toward this novel structure have been reported, involving preparative substrates and stoichiometric amounts of metal salts.9 Therefore, the design and assembly of this structurally novel fused Nheterocycle from simple materials via an elegant catalytic multicomponent strategy remains a fascinating and desirable challenge. Sodium azide (NaN3) has been extensively utilized as an inexpensive and versatile synthon in numerous organic transformations.10−13,15−18,21 Generally, synthetic procedures for incorporating an azide moiety into organic molecules © 2018 American Chemical Society
Scheme 1. Copper-Catalyzed Multicomponent Reactions Using Sodium Azide as a Dual Nitrogen Source
Received: September 25, 2018 Published: November 15, 2018 14802
DOI: 10.1021/acs.joc.8b02476 J. Org. Chem. 2018, 83, 14802−14810
Note
The Journal of Organic Chemistry quinazolin-4-amines (Scheme 1b).18 In conjunction with our ongoing research into developing copper-catalyzed multicomponent reactions using NaN3 as a dual nitrogen source, herein, we report a facile and efficient approach for the construction of structurally novel 1H-[1,2,3]triazolo[4,5-c]quinolines from commercially available 2-bromobenzaldehydes, aryl methyl ketones, and NaN3 (Scheme 1c). Notably, one C−C and four C−N bonds were formed sequentially in this copper-catalyzed domino reaction. Our initial investigation focused on the model reaction of 2bromobenzaldehyde (1a), acetophenone (2a), and NaN3 in the presence of 10 mmol % CuI, 0.2 equiv of L-proline, and 3.0 equiv of K2CO3 in DMSO at 100 °C for 20 h. Gratifyingly, the reaction proceeded to give the desired product 4-phenyl-1H[1,2,3]triazolo[4,5-c]quinoline (3a) in 26% isolated yield (Table 1, entry 1). Encouraged by this preliminary result,
(Table 1, entries 19−20). We also attempted the reaction under an argon atmosphere, but only a trace amount of 3a was observed (Table 1, entry 21). This result indicated that this transformation was assisted by oxygen. Further optimization of the reaction conditions showed that a decrease in the equivalents of NaN3, Cs2CO3, or CuBr2 catalyst gave lower yields (see the Supporting Information). Eventually, the optimal reaction conditions were determined as 1a (0.4 mmol), 1.0 equiv of 2a, 4.0 equiv of NaN3, 10 mmol % of CuBr2, 20 mmol % of L-proline, and 3.0 equiv of Cs2CO3 in 3 mL of DMSO at 100 °C in a sealed vessel under air. With the optimized conditions in hand, we proceeded to evaluate the scope and generality of this copper-catalyzed multicomponent reaction. To our delight, the reaction demonstrated a wide substrate scope in terms of the aromatic ketone unit (Scheme 2). Various aryl methyl ketones bearing
Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Scope of Aryl Methyl Ketonesa,b
entry
catalyst
base
solvent
temp (°C)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21c
CuI CuI CuI CuI CuI CuI CuI CuCl CuBr Cu2O CuCl2 CuBr2 Cu(OAc)2 Cu(OTf)2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2
K2CO3 Na2CO3 NaHCO3 Cs2CO3 K3PO4 KOH DBU Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF 1,4-dioxane toluene CH3CN DMSO DMSO DMSO
100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 90 110 100
26 19 21 67 52 trace 18 58 69 43 81 85 72 46 32 trace trace trace 62 75
